Spotted: RIPK3 and MLKL assembling necroptotic complexes
Verónica Martínez-Osorio1, Uris Ros2, Ana J García-Sáez1,2
1CECAD Cluster of Excellence Cluster at the University of Cologne , Cologne, North Rhine-Westphalia, Germany.
Open Biology
|January 27, 2026
Summary
Necroptosis, a regulated cell death pathway, involves RIPK1, RIPK3, and MLKL signaling. This review explores the structure and regulation of the RIPK3-MLKL axis, crucial for cell death execution.
Area of Science:
- Cell Biology
- Molecular Biology
- Immunology
Background:
- Necroptosis is a regulated cell death (RCD) pathway crucial for host defense against pathogens.
- It is distinct from caspase-dependent RCD and relies on RIPK1, RIPK3, and MLKL signaling.
- The RIPK3-MLKL interaction forms the necrosome, mediating cell death execution.
Purpose of the Study:
- To review the current understanding of necroptosis, focusing on the RIPK3-MLKL axis.
- To elucidate the structural organization and regulatory mechanisms governing MLKL interaction with RIPK3.
- To discuss models of necrosome assembly and activation, addressing unresolved questions.
Main Methods:
- Literature review of existing research on necroptosis.
- Analysis of structural data concerning MLKL and RIPK3 interactions.
- Synthesis of current knowledge on necrosome formation and regulation.
Main Results:
- The RIPK3-MLKL axis is central to necroptosis execution.
- Structural features of MLKL influence its binding to RIPK3.
- The high-order assembly of the necrosome and its dynamic states are not fully understood.
Conclusions:
- Further research is needed to fully resolve the structural basis and regulation of the RIPK3-MLKL interaction.
- Understanding necrosome assembly dynamics is key to comprehending necroptosis.
- This review consolidates current knowledge and highlights future research directions in necroptosis.
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